Cryptococcus gattii meningitis in a young adult in South India: A case report

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1 CASE REPORT PEER REVIEWED OPEN ACCESS Cryptococcus gattii meningitis in a young adult in South India: A case report Alagiri Sivaranjini, Sekar Uma, Kindo Anupma Jyoti, V. Shankar ABSTRACT Introduction: Cryptococcus species is one of the leading causes of invasive fungal infections in the world today. The clinical differences between the two Cryptococcus species, namely, Cryptococcus neoformans and Cryptococcus gattii depends on the ecology, epidemiology, virulence of the strain and immune status of the host. Cryptococcus gattii is an environmental fungus of the tropics and subtropics but is now known to cause sporadic infections in non-endemic regions as well. Case Report: This paper reports a case of cryptococcal meningoencephalitis in a young, immunocompetent male, in South India, which is deemed a non-endemic region for Cryptococcus gattii infections. The patient presented with sub acute symptoms of headache and visual disturbances of two months duration. Cerebrospinal fluid was sent for investigation. Diagnosis was done by demonstration of capsule by microscopy, culture, detection of capsular antigen by latex agglutination and further confirmed by gene sequencing. In spite of intensive therapy, the disease progressed rapidly and the patient succumbed to the infection. Conclusion: Cryptococcus gattii, which was reported as a fungal pathogen of the endemics, is no longer considered as an accidental pathogen. Prompt detection and timely intervention is of utmost importance in treating this serious infection. International Journal of Case Reports and Images (IJCRI) International Journal of Case Reports and Images (IJCRI) is an international, peer reviewed, monthly, open access, online journal, publishing high-quality, articles in all areas of basic medical sciences and clinical specialties. Aim of IJCRI is to encourage the publication of new information by providing a platform for reporting of unique, unusual and rare cases which enhance understanding of disease process, its diagnosis, management and clinico-pathologic correlations. IJCRI publishes Review Articles, Case Series, Case Reports, Case in Images, Clinical Images and Letters to Editor. Website: (This page in not part of the published article.)

2 Sivaranjini et al. 702 CASE case REPORT report Peer Reviewed OPEN ACCESS Cryptococcus gattii meningitis in a young adult in South India: A case report Alagiri Sivaranjini, Sekar Uma, Kindo Anupma Jyoti, V. Shankar Abstract Introduction: Cryptococcus species is one of the leading causes of invasive fungal infections in the world today. The clinical differences between the two Cryptococcus species, namely, Cryptococcus neoformans and Cryptococcus gattii depends on the ecology, epidemiology, virulence of the strain and immune status of the host. Cryptococcus gattii is an environmental fungus of the tropics and subtropics but is now known to cause sporadic infections in non-endemic regions as well. Case Report: This paper reports a case of cryptococcal meningoencephalitis in a young, immunocompetent male, in South India, which is deemed a non-endemic region for Cryptococcus gattii infections. The patient presented with sub acute symptoms of headache and visual disturbances of two months duration. Cerebrospinal fluid was sent for investigation. Diagnosis was done by demonstration of capsule Alagiri Sivaranjini 1, Sekar Uma 2, Kindo Anupma Jyoti 3, V. Shankar 4 Affiliations: 1 MBBS, Final year post graduate in MD Microbiology, Department of Microbiology, Sri Ramachandra Medical College & Research Institute, Chennai, India; 2 Professor and Head, Department of Microbiology, Sri Ramachandra Medical College & Research Institute, Chennai, India; 3 Professor, Department of Microbiolgy, Sri Ramachandra Medical College & Research Institute, Chennai, India; 4 Professor of Neurology, Sri Ramachandra Medical College & Research Institute, Chennai, India. Corresponding Author: Dr. Anupma Jyoti Kindo, Professor, Department of Microbiology, Sri Ramachandra Medical College & Research Institute, Porur, Chennai, Tamilnadu. India ; Ph: ; anupmalakra@ gmail. com Received: 02 July 2015 Accepted: 22 August 2015 Published: 01 November 2015 by microscopy, culture, detection of capsular antigen by latex agglutination and further confirmed by gene sequencing. In spite of intensive therapy, the disease progressed rapidly and the patient succumbed to the infection. Conclusion: Cryptococcus gattii, which was reported as a fungal pathogen of the endemics, is no longer considered as an accidental pathogen. Prompt detection and timely intervention is of utmost importance in treating this serious infection. Keywords: Cryptococcus gattii, Cryptococcus neoformans, Invasive fungal infections, Meningitis How to cite this article Sivaranjini A, Uma S, Jyoti KA, Shankar V. Cryptococcus gattii meningitis in a young adult in South India: A case report. Int J Case Rep Images 2015;6(11): doi: /ijcri cr INTRODUCTION Invasive fungal infections are a significant threat to immunocompromised patients. Recently, reports of systemic mycosis in previously healthy individuals are on the rise [1]. This may be attributed to the evolution of the fungal pathogens with increased virulence. This necessitates a high index of suspicion for fungal infections with atypical presentations. Cryptococcus neoformans species complex belongs to the phylum Basidiomycota. These group of yeasts can cause fatal infections of the central nervous system, lung and skin not only in humans but also in animals.

3 C. neoformans var. grubii (serotype A) and C. neoformans var. neoformans (serotype D) have been isolated worldwide, causing disease in immunocompromised hosts. C. neoformans var. gattii (serotype B and C), has been recently elevated to species level as Cryptococcus gattii, due to its phenotypic and molecular differences [2, 3]. Moreover, C. gattii infects mainly immunocompetent hosts. It is an environmental fungus, first isolated in Vancouver Islands, British Columbia in By two decades, it has been associated with 176 cases and 8 deaths worldwide [3, 5]. This fungi is generally restricted geographically to the tropical and subtropical climates [6]. It spreads through the inhalation of spores. It is known to produce large space occupying lesions. The sequencing of the genomes of the two species reveals distinct functional differences in similar genes. The microevolution in the genome of C. gattii has lead to a change in its ecological niche and its virulence factors, which explains reports of sporadic cases of C. gattii infections in non-endemic regions [6]. C. gattii meningitis requires a more aggressive and longer duration of therapy when compared to Cryptococcus neoformans. Though reported rarely, prevalence of C. gattii infections is now on the rise [7]. This paper describes a case of primary central nervous system (CNS) cryptococcosis caused by C. gattii. The infection was diagnosed by detection of Cryptococcal capsular antigen and demonstration of capsulated yeast cells in negative staining microscopy and further confirmed by culture and gene sequencing. Sivaranjini et al. 703 yeasts, compatible with Cryptococcus species (Figure 2). Fungal culture of the CSF sample on Sabouraud s dextrose agar yielded cream colored, mucoid colonies, which were identified as Cryptococcus gattii by VITEK 2 (BioMerieux, Inc, Durham NC, USA. panel YST ) (Figure 3). The identification was further confirmed by gene sequencing. The sequence has been submitted to the databank. The accession number is Banklt Cryptococcus KT The patient was started on Injection amphotericin B for treatment of meningitis, but since he developed anaphylactic reaction to it, the medication was discontinued. Fluconazole 400 mg per day plus flucytosine100 mg/kg/d in 4 divided doses was given since this patient was unable to tolerate amphotericin B. He was put on mechanical ventilation. A therapeutic lumbar puncture was done to decrease the raised intracranial pressure. A repeat CT brain, done at this point of time, revealed diffuse cerebral edema (Figure 4). A repeat MRI could not be performed. The patient s condition deteriorated through a period of 16 days. Cardiopulmonary decompensation and superadded bacterial infections worsened his condition. CASE REPORT A 24-year-old unmarried male presented to our hospital with chief complaints of headache, bilateral visual disturbance (diplopia), photosensitivity and intermittent fever. He was an engineering graduate by profession, with no history of travel in the previous 5 years. He gave no history of association with animals. His residence was not in proximity to any vegetation which might serve as a source of Cryptococcus infection. He was seronegative for retroviral infection and had no overt immunodeficiency state. It was later found that his CD4 count was below normal (292 cells/mm 3 ). On admission, his systemic examination revealed no abnormalities. Ocular examination showed bilateral lateral rectus palsy and papilledema. Computed tomography (CT) scan and magnetic resonance imaging (MRI) scan of brain were normal. As the patient developed increasing drowsiness and restlessness, he was admitted in the ICU with a provisional diagnosis of meningoencephalitis. Lumbar puncture was done in which cerebrospinal fluid pressure was high. The CSF parameters showed: sugar-3 mgs/dl, protein 73mg/dl, white blood cells 63 cells/cm 3. red blood cells 26 cells/cm 3. Gram staining of CSF revealed occasional pus cells and plenty of yeast cells with a clear halo, suggestive of capsule (Figure 1). Negative staining with India ink showed plenty of capsulated Figure 1: Gram stain of the cerebrospinal fluid showing round to oval budding yeast cells ranging from 5 20 µm in size, with clearing around them suggestive of capsule (Magnification x100). Figure 2: Direct microscopy of cerebrospinal fluid with 10% Nigrosin showing round to oval yeast cells ranging from 5 20 µm in size with a distinct halo, suggestive of capsule (Magnification, x100).

4 Sivaranjini et al. 704 Figure 3: 48 hr old culture of Cryptococcus gattii on Sabouraud Dextrose agar without actidione showing mucoid, cream colored colonies. Figure 4: Computed tomography scan of brain (plain study) showing diffuse cerebral edema. response to therapy [1, 9]. Radiographic imaging is used to identify mass lesions, which may be the primary finding in this indolent infection. Phenotypically, C. gattii is differentiated from C. neoformans by L-Canavanineglycine-bromothymol blue agar. Serotypic determination can be by slide agglutination tests. Molecular methods like PCR and gene sequencing aid in the confirmation of the isolate to species level. Cryptococcal meningitis is treated in 3 phases: Induction (AmpB plus Flucytosine for 2 weeks), Consolidation (Fluconazole for 8 weeks) and Maintenance (Fluconazole for 6 months to 1 year). The first report of C. gattii as a pathogen was in 1896 by pathologist, Ferdinand Curtis. First case of human meningitis by C. gattii was reported in 1999 in Vancouver Islands, British Columbia, Canada [5]. Nearly 60 cases of C. gattii infection have been reported in United States during the outbreak in Between 2004 and 2011, 96 cases of C. gattii infections were reported from Pacific Northwest. In India, the first case of C. gattii infection in an AIDS patient was documented by Abraham et al. [8]. Chakrabarti et al. reported five isolates of C. gattii from eucalyptus trees in Northern India, and traced the origin of these trees to Australia, thus validating spread of C. gattii infection in nonendemic areas [10]. Marriott et al. recorded five cases of C. gattii meningitis among seven HIV patients with cryptococcal infection [11]. Few reports of C. gattii meningitis among immunocompetent population of India and other countries are tabulated (Table 1) [12]. It is inferred that though there have been sporadic cases of C. gattii infections in immunocompetent individuals, isolated primary cerebral cryptococcosis is found to be rare. Table 1: Few Reports of cerebral Cryptococcus gattii infections in immunocompetent patients globally. Reported By Year Site Geographical Area After three weeks of intensive therapy, he succumbed to the infection. DISCUSSION Being an environmental fungus of the tropics and subtropics, Cryptococcus gattii has been reported as an accidental infection in apparently immunocompetent individuals, with history of residing in or recent travel to an endemic area like British Columbian Islands and North West Pacific Coast of America. It has a specialized ecological niche in eucalyptus and almond trees [4, 7]. C. gattii more frequently causes pulmonary infections while C. neoformans has increased cerebral tropism [8]. C. gattii meningitis is characterized by larger space occupying lesions than C. neoformans, and associated with more neurological complications increased incidence of neurosurgical intervention and delayed Zahra et al Cerebral Malta, Southern Europe Georgi et al Cerebral Zurich, Switzerland Shu Hao Chang Manoj Kumar Pranigrahi et al Disseminated (Cerebral & Cutaneous) 2010 Disseminated ( Pulmonary & Cerebral) Suchitha et al Disseminated (Cutaneous, Pulmonary & Cerebral) Rajesh T Patil et al. Olivia Cometti et al. Taichung, Taiwan Tamilnadu, India Mysore, India 2013 Cerebral Uttarakhand, India 2014 Cerebral Cuiaba, Brazil

5 The present report is a case of C. gattii meningitis in a young adult who was seronegative for HIV infection and apparently immunocompetent. He presented with indolent signs of meningitis like intensifying headaches and diplopia of two months duration, which later progressed to acute cryptococcal meningitis. Further, anaphylaxis to amphotericin B posed a hurdle in clearing the cryptococcal infection. Hence, the patient was started on fluconazole combined with flucytosine. However, the combination of fluconazole and flucytosine is clinically inferior to amphotericin B based therapy. The patient expired after 23 days of stay in the intensive care unit. CONCLUSION This case report heralds the need for suspicion of Cryptococcus gattii infection even in non-endemic regions. It contradicts the popular belief that invasive cryptococcosis is usually caused by Cryptococcus neoformans and not by Cryptococcus gattii. Environmental and clinical surveillance of cryptococcosis is important in preventing under reporting of C. gattii infections in non-endemic areas. ********* Author Contributions Sivaranjini Alagiri Acquisition of data, Analysis and interpretation of data, Drafting the article, Final approval of the version to be published Uma Sekar Substantial contributions to conception and design, Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published Anupma Jyoti Kindo Substantial contributions to conception and design, Analysis of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published V. Shankar Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published Guarantor The corresponding author is the guarantor of submission. Conflict of Interest Authors declare no conflict of interest. Copyright 2015 Sivaranjini Alagiri et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information. REFERENCES Sivaranjini et al Perfect JR. The triple threat of cryptococcosis: it s the body site, the strain, and/or the host. MBio 2012 Jul 10;3(4). pii: e Smith RM, Mba-Jonas A, Tourdjman M, et al. Treatment and outcomes among patients with Cryptococcus gattii infections in the United States Pacific Northwest. PLoS One 2014 Feb 19;9(2):e Kwon-Chung KJ, Boekhout T, Fell JW, Diaz M. Proposal to conserve the name Cryptococcus gattii against C. hondurianus and C. bacillisporus (Basidiomycota, Hymenomycetes, Tremellomycetidae). Taxon 2002;51(4): McLaughlin J. Cryptococcus gattii-an Emerging Infectious Disease in the Pacific Northwest. State of Alaska Epidemiology-Bullettin 2010; Galanis E, Waters S, Li M, Hoang L, MacDougall L, Phillips P. Cryptococcus gattii in BC: Update on an emerging disease. BCMJ 2007;49(7): Kidd SE, Hagen F, Tscharke RL, et al. A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island (British Columbia, Canada) Proc Natl Acad Sci U S A Dec 7;101(49): Springer DJ, Chaturvedi V. Projecting global occurrence of Cryptococcus gattii. Emerg Infect Dis 2010 Jan;16(1): Heitman J. Clinical perspectives on Cryptococcus neoformans and Cryptococus gattii: implications for diagnosis and management. ASM; p Cogliati M. Global Molecular Epidemiology of Cryptococcus neoformans and Cryptococcus gattii: An Atlas of the Molecular Types. Scientifica (Cairo) 2013;2013: Chakrabarti A, Jatana M, Kumar P, Chatha L, Kaushal A, Padhye AA. Isolation of Cryptococcus neoformans var. gattii from Eucalyptus camaldulensis in India. J Clin Microbiol Dec;35(12): Nagarathna S, Kumari HB, Arvind N, Prevalence of Cryptococcus gattii causing meningitis in a tertiary neurocare center from south India: a pilot study. Indian J Pathol Microbiol Oct- Dec;53(4): da Costa MM, Teixeira FM, Schalcher TR, Mioni Thielli Figueiredo Magalhães de Brito, Valério ES, Monteiro MC. Cryptococcosis, A Risk for Immunocompromised and Immunocompetent Individuals. The Open Epidemiology Journal 2013;6:9 17.

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